Leishmaniasis is one of the six major parasitic diseases in the world. Different clinical manifestations of leishmaniasis include cutaneous, mucocutaneous, diffuse cutaneous, visceral and post kala azar dermal leishmaniasis (PKDL). Out of a total of 2 million annual cases of leishmaniasis, 500,000 of them belong to the visceral leishmaniasis (VL), the most serious and potentially fatal form of leishmaniasis (Ashford R W, et al., Parasitol Today. 1992; 8:104-5). VL is caused by Leishmania donovani in Indian subcontinent, Asia and Africa, and by L. infantum or L. chagasi in the Mediterranean region and South America. There are currently no vaccines available for leishmaniasis.
The primary method for treatment of leishmaniasis has been pentavalent antimonials (SbV):Pentostam (sodium stibogluconate; SSG) and Glucantime (meglumine antimoniate). However, large-scale antimony resistant cases have been reported in regions, including North Bihar of India. Antimonial drugs suffer from many problems including numerous side effects and a long treatment period (20 mg/kg in 2 divided doses for 30 days, intramuscular i.m. or intravenous i.v.).
Amphotericin B is normally considered a secondary treatment for VL, due to its potent antileishmanial activity. Although the use of Amphotericin B (in doses of 0.75-1 mg/kg for 15 to 20 treatments results in high cure rate, this drug suffers from the need for hospitalisation for prolonged periods, high-cost and high incidence of adverse side-effects. A liposomal formulation of amphotericin B (AmBisome® by Gilead) with lower nephrotoxicity has become available, however, this drug is not only expensive, it has other drawbacks including the need for intravenous administration and temperature instability (therefore requiring cold storage).
Paromomycin is an aminoglycoside that can be used alone or in combination with antimonials drugs. Intramuscular administration of paromomycin (15 mg/kg for 20 days) in a clinical trial in India demonstrated 94% efficacy (Sundar S, et al., N Engl J Med. 2007; 356:2571-81). Another antileishmanial agent, pentamidine, requires intramuscular or intravenous administration (2 to 3 mg/kg once a day or every second day for 4 to 7 doses), with higher doses up to 15 doses used for visceral leishmaniasis. The application of this drug is also limited by its toxicity. All of the above currently available treatment options necessitate parenteral administration, and/or hospitalization. Given the poor social infrastructure in the developing countries where most leishmaniasis are found, a chemotherapy-based disease eradication program will rely on the availability of oral drug(s) that can be self-administered without hospitalization.
Miltefosine is currently the only oral treatment available for VL. However, the use of miltefosine is associated with a number of limitations, including (i) potential teratogenicity, (ii) long treatment period of 28 days which leads to poor compliance, (iii) long residence time of miltefosine in patients' plasma which potentially can lead to emergence of miltefosine-resistant parasites, and (iv) high-cost.
In VL, resistance to SSG is a problem in Bihar of India, where half of the world's VL cases are reported. The efficacy of SSG (20 mg/kg/day for 28 days) has steadily dropped from 80% to 40% between 1988 and 2002 (Croft S L, et al. Clin Microbiol Rev. 2006; 19:111-26.). In India where VL is anthroponotic (as opposed to zoonotic in other regions), mono-therapy of miltefosine could lead to rapid emergence of resistance (Bryceson A., Trop Med Int Health. 2001; 6:928-34.).
Some natural flavonoids are known to have antileishmanial and anti-malarial activities as described in Phytochemistry, 55, 481-504 (2000) and Bioorg. Med. Chem., 22, 18-45 (2014). Nevertheless, due to their unsatisfactory efficacy and bioavailability, usage of these naturally occurring compounds is limited.
More recent studies have demonstrated that amine-linked flavonoid dimers are highly effective anti-promastigotes and anti-amastigotes agents with IC50 ranging from 0.2 to 0.63 μM, rendering them as preferred compounds over naturally occurring flavonoids (Wong I L K, et al., Journal of Medicinal Chemistry. 2012; 55, 8891-8902). One of the preferred potent flavonoid dimers, compound 39 (as shown in FIG. 1) disclosed in Wong I L K et al., which has the following structure:
is also shown to be effective in reducing foot pad lesion size in L. amazonensis cutaneous leishmaniasis murine model (Wong I L K, et al., Antimicrob Agents Chemother. 2014, 58, 3379-3388). However, amine-linked flavonoid dimers are expected to have poor oral bioavailability, and hence would not provide a solution to the problems encountered in the treatment of leishmaniasis as descried above.
There is a need to provide compounds that are able to overcome at least one, but preferably more, of the problems of the prior art. It would be desirable to provide new antileishmanial agents that are effective and safe, and preferably orally bioavailable. It would be desirable to have new antileishmanial agents that are effective against both promastigotes and amastigotes.
It is an object of the invention to provide new compounds having antileishmanial activity particularly, leishmaniasis in animals with low toxicity toward the host.
It is another object of this invention to provide a method of treating mammals which are infested with protozoa parasites of the genus Leishmania, and to provide a method of preventing mammals, including humans, from parasitic infestation of parasites of the genus Leishmania. 